Biodegradable poly(alkylene oxide)-poly(p-dioxanone) block copolymer soluble in organic solvents, and drug delivery composition comprising same

ABSTRACT

The present invention relates to a biocompatible and biodegradable block copolymer of poly(alkylene oxide) and poly(p-dioxanone), which is soluble in organic solvents, and a drug delivery composition comprising the same.

This application is a 371 of PCT/KR00/00779 filed Jul. 18, 2000.

TECHNICAL FIELD

The present invention relates to a biocompatible and biodegradable blockcopolymer of poly(alkylene oxide) and poly(p-dioxanone) which is solublein organic solvents. More particularly, the invention relates to acomposition comprising the block copolymer for delivering bioactiveagents and methods of use thereof.

BACKGROUND ART

The concept of using polymers for the controlled release of active drugsand other therapeutic compounds in medical applications has emerged andbeen developed extensively in the last two decades. When polymers areused for the delivery of pharmacologically active agents in vivo, it isessential that the polymers themselves be nontoxic and degrade intonon-toxic products as the polymer is eroded by the body fluids. Manysynthetic biodegradable polymers, however, upon erosion in vivo yieldoligomers and monomers that adversely interact with the surroundingtissue. To minimize the toxicity of the intact polymer carrier and itsdegradation products, polymers have been designed based on naturallyoccurring metabolites.

Poly(lactic acid)(PLA), poly(glycolic acid)(PGA), and copolymersthereof, have been used as drug carriers in the form of microspheres,nanospheres, implants and fibers. These polymers are polyesters that,upon implantation in the body, undergo simple hydrolysis. The productsof such hydrolysis are biologically compatible and metabolizablemoieties (i.e. lactic acid and glycolic acid), which are eventuallyremoved from the body by the citric acid cycle. Drug release from thesepolymers occurs by two mechanisms. First, diffusion results in therelease of drug molecules from the implant surface. Second, subsequentrelease occurs by the cleavage of the polymer backbone, defined as bulkerosion. Several implant studies have proven these polymers safe in drugdelivery applications when used in the form of matrices, microspheres,bone implant materials, surgical sutures, and also as long termcontraceptives. Thus, these polymers have been time-tested in variousapplications and proven safe for human use. Most importantly, thesepolymers are FDA-approved for human use.

However, these polymers do have drawbacks. For example, due to theirstrong hydrophobicity they undergo hydrolysis slowly in vivo which maycause an undesirably slow rate of drug release. When the drug to bedelivered is a high molecule weight protein drug, the activity of theprotein drug is significantly lowered due to the relatively long bindingduration of the protein drug to the hydrophobic polymer. In order tosolve such problems a number of studies have been conducted to impart asuitable degree of hydrophilicity to the predominantly hydrophobic PLA,PGA or other hydrophobic biodegradable polymers by way of introducinghydrophilic polymer moieties therein. In these studies, block copolymersof PLA, PGA or other biodegradable polymers containing bicompatiblepoly(ethylene oxide) in the form of a hydrophilic polymer block, havebeen developed to obtain an improved drug delivery polymer composition(see U.S. Pat. Nos. 4,862,168, 4,452,973, 4,716,203, 5,683,723,4,942,035, 5,384,333, 5,476,909, 5,548,035, 5,702,717, 5,449,513,5,510,103, and 5,543,158)

Doddi et al. (U.S. Pat. No. 4,052,988) have reported thatpoly(p-dioxanone), a polymer of 1,4-dioxane-2-one, is a new class ofbiodegradable polymer which has superior properties over other existingbiodegradble polymers that are used for the purpose of preparingsurgical sutures. To further improve the rheological properties ofpoly(dioxanone) for suture applications there have also been developedpoly(p-dioxanone) copolymers (see U.S. Pat. Nos. 4,643,191, 5,080,665,and 5,019,094).

However, the above-mentioned homopolymers and copolymers of p-dioxanoneare not soluble in common organic solvents which renders them notsuitable to be used as biocompatible/biodegradable drug carriers.

DISCLOSURE OF THE INVENTION

The present invention provides a biocompatible and biodegradable blockcopolymer of p-dioxanone and alkylene oxide, which is soluble in commonorganic solvents and is suitable for use as a drug delivery carrier.

The present invention also provides a composition and a formulation fordrug delivery comprising said block copolymer.

The block copolymer of the present invention, which is soluble inpharmaceutically acceptable solvents, comprises one or morepoly(alkylene oxide) blocks and one or more blocks of a p-dioxanonehomopolymer or copolymer, wherein the amount of the poly(alkylene oxide)blocks is within a range of 25 to 85% by weight, based on the totalamount of the block copolymer.

Before the present block compolymer composition and method of use indelivery of a bioactive agent are disclosed and described, it is to beunderstood that this invention is not limited to the particularconfigurations, process steps, and materials disclosed herein as suchconfigurations, process steps, and materials may vary somewhat. It isalso to be understood that the terminology employed herein is used forthe purpose of describing particular embodiments only and is notintended to be limiting since the scope of the present invention will belimited only by the appended claims and equivalents thereof.

It must be noted that, as used in this specification and the appendedclaims, the singular form “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to a polymer containing a “block” includes reference to two ormore of such blocks, and reference to “a drug” includes reference to twoor more of such drugs.

As used herein, the term “drug” or “bioactive agent” or any othersimilar term means any chemical or biological material or compoundsuitable for administration by methods previously known in the artand/or by the methods taught in the present invention and that induce adesired biological or pharmacological effect, which may include but isnot limited to (1) having a prophylactic effect on the organism bypreventing an undesired biological effect, such as preventing aninfection, (2) alleviating a condition caused by a disease, for example,alleviating pain or inflammation caused as a result of disease, and/or(3) either alleviating, reducing, or completely eliminating a diseasefrom the organism. The effect may be local, such as providing for alocal anaesthetic effect, or it may be systemic. This invention is notdrawn to novel drugs or to new classes of bioactive agents. Rather it islimited to the compositions and methods of delivery of agents that existin the state of the art or that may later be established as activeagents and that are suitable for delivery by the present invention. Suchsubstances include broad classes of compounds normally delivered intothe body. In general, this includes but is not limited to antiinfectivesuch as antibiotics and antiviral agents; analgesics and analgesiccombinations; anorexics; antihelminthics; antiarthritics; antiasthmaticagnets; anticonvulsants; antidepressants; antidiabetic agents;antidiarrheals; antihistamines; antiinflammatory agents; antimigrainepreparations; antinauseants; antineoplastics; antiparkinsonism drugs;antipruritics; antipsychotics; antipyretics; antispasmodics;anticholinergics; sympathomimetics; xanthine derivatives; cardiovascularpreparations including potassium and calcium channel blockers,beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensives;diuretics and antidiuretics; vasodilators including general coronary,peripheral and cerebral, central nervous systemstimulants;vasoconstrictors; cough and cold preparations, includingdecongestants; hormones such as estradiol and other steroids, includingcorticosteriods, hypnotics, immunosuppressive, muscle relaxants;parasympatholytics, psychostimulants; sedatives; and tranquilizers. Bythe method of the present invention, both ionized and nonionized drugsmay be delivered, as can drugs of either high or low molecular weight.Also included in the scope of these terms are nucleic acids, such asDNA, RNA, and oligonucleotides.

As used herein “effective amount” means an amount of a drug or bioactiveagent that is nontoxic but sufficient to provide the desired local orsystemic effect and performance at a reasonable benefit/risk ratio thatwould attend any medical treatment.

As used herein “peptide” means a peptide of any length and includesproteins. The terms “polypeptide” and “oligopeptide” are used hereinwithout any particular intended size limitation, unless a particularsize is otherwise specified. Typical of peptides that can be utilizedare those selected from the group consisting of oxytocin, vasopressin,adrenocorticotrophic hormone, epidermal growth factor, prolactin,luliberin or luteinising hormine releasing hormone, growth hormone,growth hormone releasing factor, insulin, somatostatin glucagon,interferon, gastrin, tetragastrin, pentagastrin, urogastroine, secretin,calcitonin, enkephalins, endorphins, angiotensins, renin, bradykinin,bacitracins, polymixins, colistins, tyrocidin, gramicidines, andsynthetic analogues, modifications and pharmacologically activefragments thereof, monoclonal antibodies and soluble vaccines. The onlylimitation to the peptide or protein drug which may be utilized is oneof functionality.

As used herein, “administering” and similar terms mean delivering thecomposition to the individual being treated such that the composition iscapable of being circulated sytemically to the parts of the body wherethe composition binds to the target cells and is taken up byendocytosis. Thus, the composition is preferably administeredsystematically to the individual, typically by subcutaneous,intramuscular, or intravenous means, or by intraperitonealadministration. Injectables for such use can be prepared in conventionalforms, either as a liquid solution or suspension or in a solid form thatis suitable for preparation as a solution or suspension in a liquidprior to injection, or as an emulsion. Suitable excipients include, forexample, water, saline, dextrose, glycerol, ethanol, and the like, andif desired, minor amounts of auxiliary substances such as wetting oremulsifying agent, buffers, and the like can be added.

The block copolymer of the present invention is composed of at least onehydrophilic block of poly(alkylene oxide) and at least one hydrophobicblock of a p-dioxanone homopolymer or copolymer. The block copolymer ofthe present invention is biocompatible, biodegradable and dissolvesreadily in solvents that are commonly used in the preparation ofpolymeric drug compositions. Therefore, it can be effectively employedas a carrier for delivering a drug.

Specifically, the block copolymer according to the present invention maybe represented by formulas (I), (II), (III) or (IV):

RO—A—B—OH   (I)

RO—B—A—B—OR   (II)

RO—A—B—A—OR   (III)

RO—(A—B)_(n)—OR   (IV)

Wherein R is hydrogen, an alkyl or acyl group having 1˜20 carbon atoms;n is an integer of 2 to 100; A represent a hydrophillic block selectedfrom the group consisting of a poly(alkylene oxide), such aspoly(ethylene oxide), and copolymers and block copolymers of ethyleneoxide and propylene oxide; and B represents a hydrophobic block selectedfrom the group consisting of poly(p-dioxanone), a block or randomcopolymer of 1,4-dioxanone and at least one comonomer selected from thegroup consisting of lactic acid, glycolic acid and carprolactone.

In accordance with the present invention, the content of the combinedhydrophilic polymer A block may range from 25 to 80% by weight,preferably from 30 to 70% by weight, of the block copolymer. When thecontent of the A block is below 25% by weight, the block copolymer isnot soluble in solvents commonly used in making a biodegradable polymersolution, and when the content of the A block exceeds 80% by weight ofthe block copolymer, the block copolymer may not function as a drugdelivery carrier because of its excessive water solubility.

The content of the A block is preferably controlled in such a way thatthe block copolymer has a water-solubility of less than 1.5 g/ml (at 25°C.). Representative examples of the hydrophilic polymer A block includevarious forms of poly(alkylene oxides), preferably, a water-soluble poly(ethylene oxide), a water-soluble copolymer of ethylene oxide andpropylene oxide and monoalkoxy-ended derivatives thereof. Preferably themonoalkoxy-terminated derivatives are (I), (II), (III) or (IV) and thederivatives disclosed in examples 1-7, the average molecular weight ofthe A blocks of the copolymer is within a range of 200 to 500,000Daltons, more preferably 2,000 to 50,000 Daltons, and most preferably2,000 to 20,000 daltons. When a water-soluble ethylene-propylenecopolymer is used as the A block, the ethylene content of theethylene-propylene copolymer is preferably 50 mol % or more.

Suitable hydrophobic polymer B blocks of the block copolymer of thepresent invention include poly(p-dioxanone) and may be selected from thegroup consisting of a homopolymer of 1,4-dioxane-2-one and a block orrandom copolymer of 1,4-dioxane-2-one and at least one monomer selectedfrom the group consisting of lactic acid, glycolic acid andcaprolactone. The hydrophobic B block can be hydrolysed by water,assisted by an enzyme in vivo, and thus it functions to control thedegradation rate of the block copolymer. In the case of using adioxanone copolymer as the B block, the hydrophobicity and thehydrolysis rate of the block copolymer may be controlled by adjustingthe content of the comonomer such as lactic acid, glycolic acid orcaprolactone. Specifically, the rate of degradation of the hydrophobicblock decreases as the content of lactic acid or caprolactone increases,whereas it increases as the glycolic acid content increases.Accordingly, the block copolymer of the present invention comprisingsuch hydrophobic copolymer provides a drug delivery carrier by which acontroller release of the drug can be effectively achieved.

Preferably, the average molecular weight of the hydrophobic B blocks ofthe copolymer of the present invention is within a range of 500 to100,000 Daltons, more preferably 500 to 50,000 Daltons and mostpreferably from 1,000 to 50,000 Daltons. When a copolymer of1,4-dioxane-2-one and lactic acid, glycolic acid or caprolactone is usedas the B block, the 1,4-dioxane-2 one content is preferably at least 5mol %, and more preferably is within a range of 30 to 70 mol %, based onthe total amount of monomer used in the preparation of said copolymer.

PLA, PGA and copolymers thereof have been used as the hydrophobiccomponent of the block used in preparing a drug delivery carrier.However, due to their high glass transition temperature (Tg) of about 45to 65° C. and a high modulus of about 2.0 Gpa, they have poorprocessability in the fabrication of a drug delivering carrier.Furthermore, since these polymers are amorphous, they cannot beprocessed into the form of a powder if their molecular weight is lessthan 3,000 Daltons.

In contrast, since the poly)p-dioxanone) derivative employed as thehydrophobic polymer B block in the present invention has relatively lowTg of about 10° C. a relatively low modulus of about 1.5 Gpa and acrystallinity of about 55%, it enables the block copolymer to maintain astable solid form even if its molecular weight is less than 3,000Daltons. In the present invention, it is preferred to employ apoly(p-dioxanone) due to its relatively high crystallinity.

As represented by formulas (I) to (IV), the present invention provides ablock copolymer of a hydrophilic A and a hydrophobic B polymer whereinthe A-B blocks may be linked by an ester, amide or urethane linkage, andboth the hydrophilic and hydrophobic blocks are readily degradable invivo in an aqueous environment with the aid of an enzyme. The presentblock copolymer has the significant advantage in that it can bedissolved in solvents commonly used in preparing biodegradable polymersolutions. Representative examples of solvents include methylenechloride, chloroform, ethanol, methanol, isopropanol, butanol, aceticacid, formic acid, ethyl acetate, methyl acetate, acetonitrile, acetone,1,4-dioxane, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethylsulfoxide, N-methylpyrolidone, of a mixture thereof. The preferredsolvent for the present invention is a member selected from the groupconsisting of methylene chloride, ethanol, ethyl acetate, acetonitrile,N,N-dimethyl formamide, N-methylpyrrolidone, and a mixture thereof.

The block copolymers of the present invention may be synthesized asfollows. In the presence of both a metal catalyst and a poly(alkyleneoxide), 1,4-dioxane-2-one undergoes a ring-opening polymerizationreaction, alone or together with lactide, glycolide or caprolactone togive a copolymer of formulas (I) or (II), depending on whether one endof the poly(alkylene oxide) is alkoxy-ended or hydroxy-ended. Thereaction is preferably carried out without an added solvent at atemperature ranging from 70 to 160° C., preferably from 80 to 130° C.for 3 to 24 hours. Exemplary catalysts that may be used in the abovereaction include stannous octate, tributyl aluminum, triethyl aluminum,zinc carbonate, zinc chloride and titanium chloride, preferably stannousoctate.

The synthesized block copolymer may be purified by dissolving the crudeproduct in an organic solvent, e.g., dichloromethane or chloroform,followed by adding the resulting solution to an organic solvent, e.g.,methanol or dimethyl ether, which dissolves the 1,4-dioxane-2-onemonomer but not the copolymer, to precipitate the desired copolymer. Thestructure and molecular weight of a purified copolymer may be determinedby H-NMR (nuclear magnetic resonance). FT-IR and GPC (gel permeationchromatography).

The block copolymers of formulas (III) or (IV), according to the presentinvention, may be synthesized by using the copolymers of formulas (I)and (II) in accordance with the coupling reactions (1) and (2),respectively.

2RO—A—B—OH+X—C(═O)—Y—C(═O)—X→RO—A—B—O—(═O)—Y—(C═O)—B—A—OR   (1)

nHO—A—B—OH+nX—C(═O)—Y—C(═O)—X→HO—{A—B—O—C(═O)—Y—C(═O)}_(n)—OH   (2)

Wherein X is HO, Cl, or Br, Y is —(CH₂)m— or —C₆H₄, m is an integer of 0to 12, and n is as defined previously.

The linkers that can be used in the above coupling reactions, includethose having two reactive groups in the molecule and are preferablybiocompatible compounds which can be metabolized in vivo, i.e. anorganic acid selected from the group consisting of oxalic acid, malonicacid, succinic acid, glutaric acid, adipic acid, phthalic acid, and thechloride and bromide salts thereof. When an organic acid is used, it isdesirable to employ a suitable dehydrating agent such as dicyclocarbodiimide, oxalic acid chloride, thionyl chloride or triphenylphosphine to promote the coupling reaction.

The block copolymers of formulas (III) and (IV) of the present inventionmay also be synthesized by using a diisocyanide derivative in accordancewith the urethane coupling reactions (3) and (4), respectively:

RO—A—B—OH+HO—A—O+O═C═N—Y—N═C═O→RO—A—B—O—C(═O)—NH—Y—NH—C(═O)—O—A—OR   (3)

nHO—A—B—OH—nO═C═N—Y—N═C═O→HO—{A—B—O—C(═O)—NH—Y—NH—C(═O)—O—B}_(n)—OH  (4)

Wherein Y and n are as defined previously.

Since the poly(p-dioxanone)-poly(alkylene oxide) block copolymer of thepresent invention is dissolvable in either an organic solvent or aqueousorganic solvent, it is possible to convert the block copolymer of thepresent invention into one of the following forms: a microsphere,microcapsule, nanosphere, nanocapsule, polymer micelle, strip, filmstick, fiber, gel, sol and the like, and be used as drug deliverycarriers.

The A—B type diblock copolymer of the present invention is useful in thepreparation of a nanosphere or polymer micelle carrying a poorly solubledrug, which may be injected intravenously, for sustained release of thedrug in the blood. The nanosphere or polymer micelle compositionpreferably has a particle size ranging from 10 to 600 nm, and morepreferably from 10 to 300 nm. Examples of poorly soluble drugs includeanti-cancer drugs such as paclitaxel, cisplatin, caboplatin,doxorubicin, camtotecin, 5-fluorouracil, cytosine, arabinose,methotrexate, antiphlogistic anodynes such as indomethacin, probiprofen,ketoprofen, piroxicam, diclofenac, and antibiotics such as cyclosporine,etraconazole, ketoconazole, tetracycline, minocycline, doxycycline,ofloxacin, ciprofloxacin, gentamicin, amphotericin B and the like.

The A—B—A or B—A—B type triblock copolymer and the (A—B)_(n) typemultiblock copolymer may used in the preparation of a drug compositionin the form of a microsphere, microcapsule, film, strip, implantformulation, polymer gel or sol containing a physiologically activeingredient prepared by conventional methods, e.g., solvent evaporation,spray dry or solvent extraction. A formulation prepared from the abovecomposition may be injected or implanted into subcutaneous tissue ormuscle for the sustained release of the physiologically activeingredient. Suitable physiologically active ingredients include peptideor protein drugs, anti-cancer drugs, antiphlogistic anodynes,antibiotics, growth hormones such as human growth hormone, procinegrowth hormone, bovine growth hormone and the like; growth factors suchas leukocyte promoting factors, erythocyte prompting drugs, osteogeneticproteins, platelet sensitive agents, epithelial cell growth factors,brain growth factors and the like, LH—RH agonist such as leuprorelinacetate goserelin acetate and the like, other peptides such as insulin,glucagons, octreotide, calcitonin, decapeptyl, follicle-stimulatinghormone, interferon and the like, sex hormones such as testosterone,progesterone, estradiol, estrogen and the like, vaccines, and genes.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Examples and Comparative Examples are provided forpurposes of illustrating certain aspects of the present invention onlyand they are not to be construed as limiting the scope of the presentinvention in any way.

EXAMPLE 1

This example illustrates the preparation of a mPEG-PDO[poly(p-dioxanone)] diblock copolymer according to formula I.

5 g (0.025 mmole) of poly(ethylene glycol) monomethyl ether (Mw mPEG2,000 daltons) was added in a 2-necked 100 ml round-bottomed flask anddried in a dry nitrogen atmosphere under reduced pressure (1 mmHg) at100° C. for 3 hours. Using a syringe, 10.3 mg of stannous octoate intoluene, which is an amount corresponding to 1.0 mol % of poly(ethyleneglycol) monomethyl ether was added into the flask. The resulting mixturewas stirred for 30 minutes and toluene was removed at 110° C. under areduced pressure(1 mmHg). To this was added 5 g of purified1,4-dioxane-2-one and the mixture was allowed to react at 80° C. for 24hours.

The polymer thus obtained was dissolved in dichloromethane, and diethylether was added thereto, with stirring, to induce preparation of thepolymer. The precipitated polymer was dried in a vacuum oven for 48hours in order to obtain an mPEG-PDO diblock copolymer(Mw 2,000-1,180Daltons), where the poly(p-dioxanone) (PDO) block had an averagemolecular weight of 1,180 Daltons and the mPEG content of this copolymerwas 62.9 wt %.

EXAMPLE 2

This example illustrates the preparation of a mPEG-PDO diblock copolymeraccording to formula I.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol) monomethyl ether(Mw 2,000 Daltons). 7.5 g of 1,4-dioxane-2-oneand 10.13 mg of stannous octate to obtain an mPEG-PDO diblockcopolymer(Mw 2,000-1,620 Daltons). The mPEG content of this copolymerwas 55.2 wt %.

EXAMPLE 3

This example illustrates the preparation of a mPEG-PDO diblock copolymeraccording to formula I.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol) monoethyl ether(Mw 2,000 Daltons), 10 g of 1,4-dioxane-2-one and10.13 mg of stannous octoate to obtain a mPEG-PDO diblock copolymer(Mw2,000-2,100 Daltons). The mPEG content of this copolymer was 48.8 wt %.

EXAMPLE 4

This example illustrates the preparation of a mPEG-PDO diblock copolymeraccording to formula I.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol) monomethyl ether(Mw 5,000 Daltons), 10 g of 1,4-dioxane-2-oneand 4.06 mg of stannous octoate to obtain a mPEG-PDO diblockcopolymer(Mw 5,000-5,800 Daltons). The mPEG content of this copolymerwas 46.3 wt %.

EXAMPLE 5

This example illustrates the preparation of a mPEG-PDO diblock copolymeraccording to formula I.

The procedure of Example 1 was repeated using 5 g for poly(ethyleneglycol) monomethyl ether(Mw 12,000 Daltons), 10 g of 1,4-dioxane-2-oneand 1.70 mg of stannous octoate to obtain a mPEG-PDO diblockcopolymer(Mw 12,000-13,200 Daltons). The mPEG content of this copolymerwas 47.6 wt %.

EXAMPLE 6

This example illustrates the preparation of a mPEG—PDO/PLA diblockrandom copolymer according to formula I.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol) monomethyl ether (Mw 2,000 Daltons), 2.07 g of 1,4-dioxane-2-oneand 2.93 g of lactic acid and 1.70 mg of stannous octoate at a reactiontemperature of 110° C. to obtain a mPEG-PDO/PLA diblock copolymer(Mw2,000-710/1,120 Daltons). The mPEG content of this copolymer was 52.2 wt%.

EXAMPLE 7

This example illustrates the preparation of a mPEG-PDO/PLA diblockrandom copolymer according to formula I.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol) monomethyl ether(Mw 5,000 Dalton), 2.07 g of 1,4-dioxane-2-oneand 2.93 g of lactic acid and 10.13 mg of stannous octoate at a reactiontemperature of 110° C. to obtain a mPEG-PDO/PLA diblock copolymer(Mw5,000-1750/2,620 Daltons). The mPEG content of this copolymer was 53.4wt %.

EXAMPLE 8

This example illustrates the preparation of a PDO-PEG-PDO triblockcopolymer according to formula II.

The procedure of Example 1 was repeated using 10 g of poly(ethyleneglycol) (Mw 1,000 Daltons), 20 g of 1,4-dioxane-2-one and 81.0 mg ofstannous octoate to obtain a PDO-PEG-PDO triblock copolymer (Mw580-1,000 Daltons). The PEG contents of this copolymer was 46.3 wt %.

EXAMPLE 9

This example illustrates the preparation of a PDO-PEG-PDO triblockcopolymer according to formula II.

The procedure of Example 1 was repeated using 10 g of poly(ethyleneglycol) (Mw 3,400 Daltons), 40 g of 1,4-dioxane-2-one and 23.8 mg ofstannous octoate to obtain a PDO-PEG-PDO triblock copolymer (Mw3,640-3,400-3,640 Daltons). The PEG content of this copolymer was 31.8wt %.

EXAMPLE 10

This example illustrates the preparation of a PDO-PEG-PDO triblockcopolymer according to formula II.

The procedure of Example 1 was repeated using 10 g of poly(ethyleneglycol) (Mw 1,200 Daltons), 40 g of 1,4-dioxane-2-one and 6.75 mg ofstannous octoate to obtain a PDO-PEG-PDO triblock copolymer (Mw12,600-12,000-12,600 Daltons). The PEG content

EXAMPLE 11

This example illustrates the preparation of a PDO/PLA-PEG-PDO/PLAtriblock copolymer according to formula II.

The procedure of Example 1 was repeated using 10 g of poly(ethyleneglycol) (Mw 3,400 Daltons), 8.29 g of 1,4-dioxane-2-one, 11.71 g oflactic acid and 23.83 mg of stannous octoate to obtain aPDO/PLA-PEG-PDO/PLA triblock copolymer (Mw 1,290/1,710-3,400-1,290/1,710Daltons). The PEG content of this copolymer was 36.2 wt %.

EXAMPLE 12

This example illustrates the preparation of a PDO/PLA-PEG-PDO/PLAtriblock copolymer according to formula II.

The procedure of Example 1 was repeated using 10 g of poly(ethyleneglycol) (Mw 3,400 Daltons), 12.46 g of 1,4 dioxane-2-one, 7.54 g oflactic acid and 23.83 may of stannous octoate to obtain aPDO/PLA-PEG-PDO/PLA triblock copolymer(Mw 2,410/841-3,400-2,410/841Daltons. The PEG content of this copolymer was 34.3 wt %.

EXAMPLE 13

This example illustrates the preparation of a mPEG-PDO-mPEG triblockcopolymer according to formula III.

11.2 g(3.5 mmole) of the mPEG-PDO-OH(Mw 2,000-1,180 Daltons) diblockcopolymer synthesized in Example 1 and 0.4 g(4 mmole) of succinic acidchloride were added to 50 ml of absolute toluene in a container. Then, 1ml of pyridine was added to the container and the mixture was stirred at120° C. for 12 hours. Toluene was removed by evaporation and theresulting product was dissolved in dichloromethane followed byfiltration to remove the solid precipitates. The supernatant was addedto diethyl ether, and the precipitated polymer was filtered and dried invacuum for 24 hours to obtain 9.85 g of an mPEG-PDO-mPEG triblockcopolymer (yield (82.08%). The completion of the reaction was confirmedby FT-IR which showed complete disappearance of the O—H vibrationabsorption band at 3,200-3,500 cm⁻¹. The mPEG content of this copolymerwas 62.9 wt % and the average molecular weight of the copolymer is 6,360Daltons.

EXAMPLE 14

This example illustrates the preparation of a mPEG-PDO/PLA-mPEG triblockcopolymer according to formula III.

The procedure of Example 13 was repeated using 10 g(0.26 mmole) of themPEG-PDO/PLA-OH diblock copolymer synthesized in Example 6 and 0.356g(0.26 mmole) of 1,6-diisocyanohexane, to obtain a mPEG-PDO/PLA-mPEGtriblock copolymer (yield 88.8%). The mPEG content of this copolymer was52.2 wt % and the average molecular weight of the copolymer is 7,660.

EXAMPLE 15

This example illustrates the preparation of a (PDO-PEG)_(n) multiblockcopolymer according to formula IV.

The procedure of Example 13 was repeated using 10 g of theHO-PDO-PEG-PDO-OH triblock copolymer synthesized in Example 8 and 0.72g(4.6 mmole) of succinic acid chloride, to obtain 9.54 g of a(PDO-PEG)_(n) multiblock copolymer(yield 90.0%, Mw 24,000 Daltons). ThePEG content of this copolymer was 46.3 wt %.

EXAMPLE 16

This example illustrates the preparation of a mPEG-PDO/PLA diblockcopolymer according to formula I.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol) monomethyl ether(Mw 5,000 Daltons), 1 g of 1,4-dioxane-2-one,1.5 g of lactic acid and 10.13 mg of stannous octoate at a reactiontemperature of 110° C. to obtain a mPEG-PDO/PLA diblock copolymer (Mw5,000-780/1,210 Daltons). The mPEG content of this copolymer was 71.5 wt%.

EXAMPLE 17

This example illustrates the preparation of a PDO-PEG-PDO triblockcopolymer according to formula II.

The procedure of Example 1 was repeated using 10 g of poly(ethyleneglycol) (Mw 3,400 Daltons), 8 g of 1,4-dioxane-2-one and 23.8 mg ofstannous octoate at a reaction temperature of 80° C. to obtain aPDO-PEG-PDO (Mw 720-3,400-720 Daltons). The PEG content of thiscopolymer was 70.2 wt %.

EXAMPLE 18

This example illustrates the preparation of a mPEG-PDO diblock copolymeraccording to formula I.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol) monomethyl ether(Mw 2,000 Daltons), 40 g of 1,4-dioxane-2-oneand 10.13 mg of stannous octoate at a reaction temperature of 80° C. toobtain a mPEG-PDO diblock copolymer(Mw 2,000-9,520 Daltons). The mPEGcontent of this copolymer was 17.4 wt %.

EXAMPLE 19

This example illustrates the preparation of a PDO-PEG-PDO triblockcopolymer according to formula II.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol)(Mw 1,000 Daltons), 35 g of 1,4-dioxane-2-one and 40.5 mg ofstannous octoate at a reaction temperature of 100° C. to obtain aPDO-PEG-PDO triblock copolymer (Mw 2,100-1,000-2,100 Daltons). The PEGcontent of this copolymer was 19.2 wt %.

EXAMPLE 20

This example illustrates the preparation of a mPEG-PDO diblock copolymeraccording to formula I.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol) monomethyl ether (Mw 2,000 Daltons), 2.08 g of 1,4-dioxane-2-oneand 10.13 mg of stannous octoate at a region temperature of 100° C. toobtain a mPEG-PDO diblock copolymer(Mw 2,000-480 Daltons). The mPEGcontent of this copolymer was 81.0 wt %.

EXAMPLE 21

This example illustrates the preparation of a PDO-PEG-PDO triblockcopolymer according to formula II.

The procedure of Example 1 was repeated using 5 g of poly(ethyleneglycol)(Mw 3,400 Daltons), 0.6 g of 1,4-dioxane-2-one and 23.8 mg ofstannous octoate at a reaction temperature of 80° C. to obtain aPDO-PEG-PDO triblock copolymer (Mw 200-3,400-200 Daltons). The PEGcontent of this copolymer was 89.0 wt %.

EXAMPLE 22

This example illustrates the solubilities of the copolymers of thepresent invention in various solvents.

The solubilities of the block polymers synthesized in Example 1 to 21 indichloromethane, chloroform, acetic acid, acetone, and distilled waterwere measured and the results are shown in Table 1.

TABLE 1 Solubility of block copolymers Example Aectic No.Dichloromethane Chloroform acid Acetone Water 1 ◯ ◯ ◯ ◯ Δ 2 ◯ ◯ ◯ ◯ X 3◯ ◯ ◯ ◯ X 4 ◯ ◯ ◯ ◯ X 5 ◯ ◯ ◯ ◯ X 6 ◯ ◯ ◯ ◯ ◯ 7 ◯ ◯ ◯ ◯ X 8 ◯ ◯ ◯ ◯ X 9◯ ◯ ◯ ◯ X 10 ◯ ◯ ◯ ◯ X 11 ◯ ◯ ◯ ◯ X 12 ◯ ◯ ◯ ◯ X 13 ◯ ◯ ◯ ◯ X 14 ◯ ◯ ◯ ◯X 15 ◯ ◯ ◯ ◯ X 16 ◯ ◯ X X X 17 ◯ ◯ ◯ ◯ ◯ 18 X X X X X 19 X X X X X 20 ◯◯ ◯ ◯ ◯^(a)) 21 ◯ ◯ ◯ ◯ ◯^(b)) ◯ freely soluble, Δ soluble, Xpractically insoluble ^(a))solubility of 1.8 g/mL, ^(b))solubility of2.0 g/mL

EXAMPLE 23

This example illustrates the preparation of mPEG-PDO diblock copolymersmicrospheres.

An 0.85 g sample of the mPEG-PDO diblock copolymer(Mw 5,000-5,800Daltons) synthesized in Example 4 was dissolved in 2 ml ofdichloromethane and 0.15 g of ofloxacin was suspended therein. Thesuspension was added to a 1 wt % polyvinylalcohol aqueous solution andstirred at 1,200 rpm for 3 hours to obtain a microsphere solution. Themicrosphere solution obtained was freeze-dried to obtain microsphereshaving an average particle size of 10 μm and containing 14.6 wt %ofloxacin.

EXAMPLE 24

This example illustrates the preparation of mPEG-PDO diblock copolymernanospheres.

An 0.85 g sample of the mPEG-PDO diblock copolymer (Mw 2,000-2,100Daltons) synthesized in Example 3 and 0.15 g of pacitaxel were dissolvedin 5 ml of acetone and 15 ml of distilled water, heated to 60° C. toobtain a clear solution which was then stirred at 600 rpm for 1 hour 15ml of distilled water was added thereto and the solution was passedthrough a 0.8 mm membrane filter. The filtrate obtained was freeze-driedto obtain nanospheres having an average particle size of 0.45 μm andcontaining 13.6 wt % pacitaxel.

EXAMPLE 25

This example illustrates the preparation of a mPEG-PDO/PLA diblockcopolymer micelle.

An 0.85 g sample of the mPEG-PDO/PLA diblock copolymer(Mw2,000-710/1,120 Daltons) synthesized in Example 6 and 0.01 g ofpaclitaxel were dissolved in 0.2 ml of acetone and 2 ml of distilledwater was added thereto to obtain a clear solution. The solution thusobtained was filtered and the filtrate was freeze-dried to obtainnanospheres having an average particle size of 0.45 μm and containing13.6 wt % paclitaxel.

EXAMPLE 26

This example illustrates the preparation of PDO/PLA-PEG-PDO/PLA triblockcopolymer microspheres.

An 0.80 g sample of the PDO/PLA-PEG-PDO/PLA triblock copolymer(Mw1,290/1,710-3,400-1,290/1,710 Daltons) synthesized in Example 11 and 0.2g of paclitaxel were dissolved in 2 ml of dichloromethane andmicrospheres having an average particle size of 48 μm and containing19.3 wt % paclitaxel were prepared in accordance with the procedure ofExample 16.

EXAMPLE 27

This example illustrates the preparation of PDO/PLA-PEG-PDO/PLA triblockcopolymer microspheres.

A 2.40 g sample of the PDO/PLA-PEG-PDO/PLA triblock copolymer(Mw1,290/1,710-3,400-1,290/1,710 Daltons) synthesized in Example 11 and 0.6g of human growth hormone were dissolved in 10 ml of acetic acid andfreeze-dried to obtain a powder. The powder thus obtained was pressedunder a pressure of 2 ton/cm² to prepare a 1 mm×10 mm cylindrical piece.The cylindrical piece was added to 5 ml of phosphate buffer solution(10M, pH 7.4) and the amount of the growth hormone released in the buffersolution was measured while shaking at 37° C. and 50 rpm. The resultsare shown in Table 2.

TABLE 2 Cumulative amount of drug released in buffer solution Time(days) Drug released (%) 1 12 3 27 5 39 7 48 9 53 11 58 13 61 15 66 1769 19 72 21 75 23 78 25 81 27 84 29 87

EXAMPLE 28

The example illustrates the preparation of a PDO-PEG-PDO triblock gel.

An 0.80 g sample of the PDO-PEG-PDO triblock copolymer (Mw3,640-3,400-3,640 Daltons) synthesized in Example 9 and 0.2 g ofpaclitaxel were dissolved in 3 ml of N-methylpyrrolidone to obtain agel. The gel was then injected in water to form a polymeric implantcontaining paclitaxel.

EXAMPLE 29

An 0.80 g sample of the mPEG-PDO diblock copolymer(Mw 2,000-480 Daltons)synthesized in Example 20 and 0.2 g of paclitaxel were dissolved in 1 mlof acetonitrile to obtain a homogeneous solution and the resultingsolution was added to 0.2% polyvinyl alcohol. However, polymericmicelles were not obtained due to the excessive solubility of thepolymer in the aqueous solution. This indicates that mPEG-PDO diblockcopolymers containing 81% by weight of mPEG are not suitable forpreparing a drug containing micelle.

EXAMPLE 30

A 1.80 g of the PDO-PEG-PDO triblock copolymer(Mw 200-3,400-200 Daltons)synthesized in Example 21 and 0.2 g of porcine growth hormone weredissolved in 1 ml of distilled water and freeze-dried to obtain polymerparticle containing the growth hormone. The polymer particles were addedto distilled water to measure the rate of drug release, but theparticles simply dissolved in water. This indicates that a PDO-PEG-PDOtriblock copolymer containing 89% by weight of mPEG are not suitable forpreparing a drug containing implant.

While the invention has been described with respect to the abovespecific embodiments, it should be recognized that various modificationsand changes may be made to the invention by those skilled in the artwhich also fall within the scope of the invention as defined by theappended claims.

We claim:
 1. A block copolymer comprising one or more poly(alkyleneoxide) blocks and one or more blocks of a p-dioxanone homopolymer orcopolymer, wherein: (a) the block copolymer has a solubility in anorganic solvent of 33.3 to 1,000 mg/ml; and (b) the poly(alkylene oxide)blocks comprise between 25% to 80% by weight of the block copolymer. 2.The block of claim 1, wherein the poly(alkylene oxide) blocks comprisesbetween 30 to 75% by weight of the block copolymer.
 3. The blockcopolymer of claim 1 having an average molecular weight of between 625to 2,000,000 Daltons.
 4. The block copolymer of claim 1, wherein thetotal molecular weight of the poly(alkylene oxide) blocks is withinrange from 200 to 500,000 Daltons.
 5. The block copolymer of claim 1,wherein the poly(alkylene oxide) is a member selected from the groupconsisting of poly(ethylene oxide), random copolymers of ethylene oxideand propylene oxide and block copolymers of poly(ethylene oxide) andpoly(propylene oxide) and monoalkoxy-terminated derivatives thereof. 6.The block copolymer claim 1, wherein the p-dioxanone copolymer is acopolymer of 1,4-dioxane-2-one and a member selected from the groupconsisting of glycolic acid, lactic acid, and caprolactone.
 7. The blockcopolymer of claim 6, wherein the p-dioxanone copolymer contains atleast 5 mole percent of repeating units derived from 1,4-dioxane-2-onebased on the total amount of monomers used in preparing said copolymer.8. The block copolymer of claim 1, wherein the block copolymer is adiblock or triblock copolymer.
 9. The block copolymer of claim 1 whereinsaid block copolymer is selected from the group consisting of RO—A—B—OH,RO—B—A—B—OR, RO—A—B—A—OR and RO— (A—B)_(n)—OR, wherein R is hydrogen, analkyl or acyl group having 1˜20 carbon atoms, n is an integer of 2 to100; A is a hydrophillic poly(alkylene oxide) block selected from thegroup consisting of poly(ethylene oxide), random copolymers of ethyleneoxide and propylene oxide and block copolymers of poly(ethylene oxide)and poly(propylene oxide); and B is a hydrophobic block selected fromthe group consisting of poly(p-dioxanone), a block or random copolymerof 1,4-dioxanone and at least one comonomer selected from the groupconsisting of lactic acid, glycolic acid and carprolactone.
 10. Theblock copolymer claim 1, wherein the organic solvent is a memberselected from the group consisting of methylene chloride, chloroform,ethanol, methanol, isopropanol, butanol, acetic acid, formic acid, ethylacetate, methyl acetate, acetonitrile, acetone, 1,4-dioxane,N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide,N-methylpyrrolidone, or a mixture thereof.
 11. A bioactive agentdelivery composition comprising the block copolymer of claim 1 and abioactive agent encased therein.
 12. The composition of claim 11,wherein the bioactive agent is a member selected from the groupconsisting of peptides or proteins, anti-cancer agents, antiphlogisticanodyme agents, anti-biotic agents, anti-bacterial agents, hormones,genes and vaccines.
 13. The composition of claim 1, wherein thebioactive agent is selected from the group consisting of paclitaxel,cisplatin, carboplatin, doxorubicin, camtotecin, 5-fluorouracil,cytosine arabinoside, methotrexate, indomethacin, probiprofen,ketoprofen, piroxicam, diclofenac, cyclosporine, etraconazole,ketoconazole, tetracycline, minocycline, doxycycline, ofloxacin,ciprofloxacin, gentamicin, amphotericin B human growth hormone, piggrowth hormone, bovine growth hormone, leukocyte increasing factors,erythrocyte increasing agent, osteogenetic protein, platelet sensitiveagent, epithelial cell growth factor, brain growth factor, leuprorelinacetate, goserelin acetate, insulin, glucagon, octreotide, calcitonin,decapeptyl, follicle-stimulating hormone, interferon, testosterone,progesterone, estradiol, estrogen.
 14. A drug formulation forsubcutaneous implantation of intravenous injection comprising thecomposition of claim
 11. 15. A drug formulation for subcutaneousimplantation or intravenous injection comprising a bioactive agentdelivery composition comprising a block copolymer comprising one or morepoly(alkylene oxide) blocks and one or more blocks of a p-dioxanonehomopolymer or copolymer, wherein: (a) the block copolymer is soluble inan organic solvent; and (b) the poly(alkylene oxide) blocks comprisebetween 25 to 85% by weight of the block copolymer; and a bioactiveagent encased therein, wherein said composition is in the form of amicrosphere, microcapsule, film, strip, fiber, gel or solution.
 16. Adrug formation for subcutaneous implantation or intravenous injectioncomprising a bioactive agent delivery composition comprising a blockcopolymer comprising one or more poly(alkylene oxide) blocks and one ormore blocks of a p-dioxanone homopolymer or copolymer, wherein: (a) theblock copolymer is soluble in an organic solvent; and (b) thepoly(alkylene oxide) blocks comprise between 25 to 80% by weight of theblock copolymer; and a bioactive agent encased therein, wherein saidcomposition is in the form of a nanosphere, nanocapsule or polymericmicelle.